Prediction of octanol-water partition coefficients for the SAMPL6-logP molecules using molecular dynamics simulations with OPLS-AA, AMBER and CHARMM force fields

Shujie Fan (1) , Bogdan Iorga (2) , Oliver Beckstein (1)

1 ASU - Department of Physics, Arizona State University
2 ICSN - Institut de Chimie des Substances Naturelles

All-atom molecular dynamics simulations with stratified alchemical free energy calculations were used to predict the octanol-water partition coefficient log P ow of eleven small molecules as part of the SAMPL6-log P blind prediction challenge using four different force field parametrizations: standard OPLS-AA with transfer-able charges, OPLS-AA with non-transferable CM1A charges, AMBER/GAFF, and CHARMM/CGenFF. Octanol parameters for OPLS-AA, GAFF and CHARMM were validated by comparing the density as a function of temperature to experimental values. The partition coefficients were calculated from the solvation free energy for the compounds in water and pure ("dry") octanol or "wet" octanol with 27 mol % water dissolved. Absolute solvation free energies were computed by thermodynamic integration (TI) and the Multistate Bennett Acceptance Ratio (MBAR) with uncorre-lated samples from data generated by an established protocol using 5-ns windowed alchemical free energy perturbation (FEP) calculations with the Gromacs molecular 2 Shujie Fan et al. dynamics package. Equilibration of sets of FEP simulations was quantified by a new measure of convergence based on the analysis of forward and time-reversed trajec-tories. The accuracy of the log P ow predictions was assessed by descriptive statistical measures such as the root mean square error (RMSE) of the data set compared to the experimental values. Discarding the first 1 ns of each 5-ns window as an equilibration phase had a large effect on the GAFF data, where it improved the RMSE by up to 0.8 log units, while the effect for other data sets was smaller or marginally worsened the agreement. Overall, CGenFF gave the best prediction with RMSE 1.2 log units, although for only eight molecules because the current CGenFF workflow for Gromacs does not generate files for certain halogen-containing compounds. Over all eleven compounds, GAFF gave an RMSE of 1.5. The effect of using a mixed water/octanol solvent slightly decreased the accuracy for CGenFF and GAFF and slightly increased it for OPLS-AA. The GAFF and OPLS-AA results displayed a systematic error where molecules were too hydrophobic whereas CGenFF appeared to be more balanced, at least on this small data set.

Mots clés: molecular dynamics; solvation free energy; OPLS-AA force field; AMBER force field; CHARMM force field; ligand parametrization; free energy perturbation; octanol-water partition coefficient

Domaines: Chimie théorique et/ou physique

Shujie Fan, Bogdan Iorga, Oliver Beckstein. Prediction of octanol-water partition coefficients for the SAMPL6-logP molecules using molecular dynamics simulations with OPLS-AA, AMBER and CHARMM force fields. Journal of Computer-Aided Molecular Design, 2020, 34 (5), pp.543-560. ⟨10.1007/s10822-019-00267-z⟩. ⟨hal-02566072⟩